6270
the reduction of the sulfenyl chloride group is accomplished, but not the cyclization to the thiazolidine ring, In order to prepare the corresponding 5-epipenicillin with a free carboxyl group in the molecule, a similar reductive cyclization starting with the benzhydryl ester l b has been carried out. Esterification of 6-phthalimidopenicillanic acid with diphenyldiazomethane gives the appropriate benzhydryl ester as colorless silky needles, mp 161-163", [ a ] ~ +230.6" (CHCIB). Treatment of this ester with chlorine in methylene chloride at 0" for 30 min yields l b as an amorphous solid, nmr (CDCI,) 100 (s, 3 H), 104 ( s , 3 H), 288 ( s , 1 H), 328 (d, 1 H, J = 1.5 Hz), 360 (d, 1 H, J = 1.5 Hz), 422 (s, 1 H), 443 (m, 10 ArH), and 469 Hz (m, 4 ArH), in almost quantitative yield. Reductive cyclization of l b with anhydrous stannous chloride in tetrahydrofuran at room temperature for 2 hr yields a crude mixture of 3b and 4b in the ratio of ca. 1O:l. After separation by chromatography on silica gel, a colorless noncrystalline solid 3b is isolated: [ ~ J D -75" (CHCI3); Y:::'~ 1796 (azetidinone CO), 1785 and 1735 (phthalimido CO), and 1745 cm-I (ester CO). The trans orientation of the azetidinone protons in 3b is clearly established by doublets at 328 and 335 Hz and their coupling constant (J = 2.0 H z ) . ~ The unchanged S configuration at C-3 is ascertained by measuring an internal nuclear Overhauser effect (NOE). Upon irradiation of the low-field methyl protons (99 cps), the H-3 signal at 240 Hz is increased by 17,6%, whereas saturation of the high-field methyl signal (76 Hz) does not increase the intensity of the H-3 peak. If we assume the assignment of Cooper, et al.,1° for the 2p and 2a methyl groups, the observed relaxation of H-3 is due to the 2p methyl protons and the configuration at the chiral center 3 is S. Cleavage of ester 3b with trifluoroacetic acid in anisole at 0" for 10 min gives 6-phthalimido-5-epipenicillanic acid (3c) as a colorless solid: [ a ] ~ - 103.5" (CHCl,); v;:Ei3 1795 (azetidinone CO) and 1782 and 1735 cm-' (phthalimido CO). The coupling constant ( J = 2.0 Hz) for the azetidinone doublets at 324.5 and 330.5 Hz indicates the trans stereochemistry of the corresponding protons. The S configuration of C-3 is again affirmed by internal NOE. The intensity of the H-3 singlet at 238.5 Hz is increased by 15.4% after irradiation of 29 CH3 protons at 103 Hz, but there is no relaxation of H-3 upon irradiation of 2 a CH3 protons (94 Hz). A plausible mechanism for the reduction of 1 with stannous chloride to 2 as well as the subsequent cyclization to 3 and 4 can be explained by electron transfer from tin(I1) to the sulfur as shown in 5. In the case of COOR
Sn
5
COOR I
COOR
Sn
6
7
(9) D. A. Johnson and D. Mania, Terrahedron Lett., 267 (1969), and references cited therein. (10) R . D. G. Cooper, P. V. Demarco, J. C. Cheng, and N. D. Jones, J . Amer. Chem. SOC.,91, 1408 (1969); R. D. G. Cooper, P.V. Demarco, and D. 0. Spry, ibid., 91, 1528 (1969).
reduction, probably the hydrolysis of intermediate 5 takes place. We have indeed observed that the reduction of 1 to 2 is facilitated by increasing the polarity of solvent and that the reaction is terminated at this step. However, in an aprotic solvent most likely a stabilized carbonium ion 7 is formed uia 6 and subsequently cyclized to 3 and/or 4. The high stereoselectivity of reductive cyclization can be explained by the bulkiness of the neighboring phthalimido group. The present work describes the synthesis of the fourth isomer of penicillin. By applying the described methods for ring opening and closure of the penicillin molecule and the known epimerization of (2-6, other stereoisomeric penicillins can be synthesized. The described 6-phthalimido-5-epipenicillanicacid is devoid of antibiotic activity. Stjepan Kukolja The Lilly Research Laboratories, Eli Lilly and Company Indianapolis, Indiana 46206 Received August 2 , 1971
Structure Analysis by Carbon-13 Nuclear Magnetic Resonance Spectroscopy. Arenahe' Sir : We wish to report the structure determination of an organic natural product of unknown constitution in which a natural abundance l3C nmr spectral analysis plays a major role. The seeds of Plantago arenaria Waldst and Kit. have yielded2 narcotine and a new CllH170N3alkaloid, ~ (c 1.7, chloroarenafne, mp 208-210"; [ a ] 2 2+305" form); m/e 207.1367 (calcd 207.1372);3 uv (ethanol) A,, 213 (3.81), 244 nm (log B 4.07); ir N H 2.90 (m), 3.25 (m), C=O 6.09 p (s). The 220-MHz pmr spectrum of arenaine reveals methyl [6 1.50 (s)] and vinyl [5.33 ( d , J = 11 Hz), 5.36 ( d , J = 18 Hz), 5.98 ( d d , J = 11, 18 Hz)] groups on quaternary carbon sites, a methyl function [1.15 (d, J = 6.5 Hz)] on a methine center, and several difficultly interpretable multiplets. The presence of monoterpene alkaloids in various Plantago species4 and representation of the unusual CllN3 combination in the guanidyl monoterpene chaksine5 suggests that arenaine may possess a related structure. Application of chemical-shift theory6 to the noise resonance decoupled and single frequency decoupled spectra' of a chloroform solution of arenaine shows (1) Carbon-13 Nuclear Magnetic Resonance Spectroscopy of Naturally Occurring Substances. VI. Previous publications: F. R. N. Gurd, P. J. Lawson, D. W. Cochran, and E. Wenkert, J . B i d . Chem., 246, 3725 (1971); A. Allerhand, D. Doddrell, V. Glushko, E. Wenkert, P. J. Lawson, and F. R. N. Gurd, J . Amer. Chem., 93, 544 (1971); E. Wenkert, C.-J. Chang, A. 0. Clouse, and D. W. Cochran, Chem. Commun., 961 (1970); E . Wenkert, A. 0. Clouse, D. W. Cochran, and D. Doddrell, ibid., 1433 (1969); E. Wenkert, A. 0. Clouse, D. W. Cochran, and D. Doddrell, J . Amer. Chem. Soc., 91,6879 (1969). (2) J. Peyroux, M. Hachem-Mehri, M. Platt, P. Rossignol, and G. Valette, Ann. Pharm. Fr., in press. (3) The authors are indebted to Dr. B. C. Das (I.C.S.N., Gif-surYvette) for the mass spectral determination. (4) A. V. Danilova and R. A. Konovalova, Zh. Obshch. Khim., 26, 2307 (1956); R. Torsell, Acta Chim. Scand., 22, 2715 (1968); Z. F. Ahmed, A. H. Rizk, and F. M. Hammouda, J . Pharm. Pharmacol., 17, 395 (1965). ( 5 ) L. R . Fowler, Z. Valenta, and I
